Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors which are expressed in many regions of the brain. D1 mRNA has been found, for example, in the striatum and nucleus accumbens. See e.g., Missale C, Nash S R, Robinson S W, Jaber M, Caron M G “Dopamine receptors: from structure to function”, Physiological Reviews 78:189-225 (1998). Pharmacological studies have reported that D1 and D5 receptors (D1/D5), namely D1-like receptors, are linked to stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors, namely D2-like receptors, are linked to inhibition of cAMP production.
Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. For example, D1 receptors are involved in different types of memory function and synaptic plasticity. See e.g., Goldman-Rakic P S et al., “Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction”, Psychopharmacology 174(1):3-16 (2004). Moreover, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), schizotypal personality disorder, cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia, Parkinson's disease (PD), Huntington's chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g., Goulet M, Madras B K “D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys”, Journal of Pharmacology and Experimental Therapy 292(2):714-24 (2000); Surmeier D J et al., “The role of dopamine in modulating the structure and function of striatal circuits”, Prog. Brain Res. 183:149-67 (2010).
New or improved agents that modulate (such as agonize or partially agonize) D1R are needed for developing new and more effective pharmaceuticals to treat diseases or conditions associated with dysregulated activation of D1R, such as those described herein.
US20040167336 or WO2002024695 reports octahydroindolizine, octahydroquinolizine and hexahydro-pyrrolizine derivatives of the following formula:
their synthesis and their use as histaminic H1 and H3 antagonists, for example, for the treatment of disorders and conditions mediated by the histamine receptor.
US20120245172 or WO2012126922 reports heterocyclic amine derivatives of the following formula:
as TAAR ligands useful in the treatment of TAAR related disease.
CN102558147 reports pyridinecarboxamide derivatives of the following formula:
as inhibitors of tyrosine kinase and/or serine-threonine kinase for treating cancer.
US20130123284 or WO2011119894 reports compounds of the following formula:
or N-oxide, N,N′-dioxide, N,N′,N″-trioxide, or pharmaceutically acceptable salts thereof as kinase inhibitors useful for treating, for example, lymphangiogenesis, angiogenesis and/or growth of a tumor.
WO2007009524 reports 2-arylbenzothiazoles of the following formula
useful as protein kinase inhibitors for treating diseases such as those associated with abnormal and hyperproliferation of cells.
Kim, Eun-sook et. al, “Design, syntheses and biological evaluations of nonpeptidic caspase 3 inhibitors,” Bulletin of the Korean Chemical Society (2002), 23(7), 1003-1010, reports design of certain scaffold for nonpeptidic caspase 3 Inhibitors, for example, compounds of the following formulas:

In addition, certain compounds of the following formula of
(wherein X is H, OCH3, Cl, CN, NO2, or Ph) were prepared. But they didn't show inhibitory activities on caspase 3.